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<p>Focal cortical dysplasias (FCDs) are a major cause of drug-resistant epilepsy, yet their molecular and pathological complexity has limited the development of effective antiseizure medications. Here, we performed single-nucleus RNA sequencing on 49 human neocortical specimens spanning FCDI<i>-</i>III. We identified prominent transcriptional alterations in non-neuronal populations, particularly astrocytes and vascular cells, with signatures suggestive of endothelial and smooth muscle cell dysfunction. In contrast, neuronal populations exhibited additional subtype-specific heterogeneity. Notably, vascular-associated signatures were consistently observed across FCD subtypes, suggesting a convergent feature of diseased cortex. To systematically explore candidate interventions, we integrated cell-type-resolved transcriptional signatures with the Connectivity Map to prioritize compounds from ~40,000 perturbagens. This analysis yielded 20 candidates, among which four compounds (Betamethasone, Lodamin, Valproxam, and Licochalcone A) reduced seizure-like activity in vivo, as assessed by behavioral assays and local field potential recordings. These effects were further evaluated in an mTOR-driven FCD model. Collectively, our findings establish a transcriptome-guided framework for linking multicellular disease signatures to candidate therapeutic strategies in refractory epilepsy.</p>

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Single-nucleus transcriptomics-based drug screening platform for focal cortical dysplasia

  • 期刊论文

  • 发表日期：

    2026年7月11日

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  • Chuantao Fang,
  • Guilin Meng,
  • Lin Yang,
  • Lijun Wang,
  • Yanfeng Tan,
  • Jingjing Guo,
  • Ying Shi,
  • Xianming Liu,
  • Rui Zhao,
  • Min Zhang,
  • Lei An,
  • Fang Yuan,
  • Dashi Qi

摘要

Focal cortical dysplasias (FCDs) are a major cause of drug-resistant epilepsy, yet their molecular and pathological complexity has limited the development of effective antiseizure medications. Here, we performed single-nucleus RNA sequencing on 49 human neocortical specimens spanning FCDI-III. We identified prominent transcriptional alterations in non-neuronal populations, particularly astrocytes and vascular cells, with signatures suggestive of endothelial and smooth muscle cell dysfunction. In contrast, neuronal populations exhibited additional subtype-specific heterogeneity. Notably, vascular-associated signatures were consistently observed across FCD subtypes, suggesting a convergent feature of diseased cortex. To systematically explore candidate interventions, we integrated cell-type-resolved transcriptional signatures with the Connectivity Map to prioritize compounds from ~40,000 perturbagens. This analysis yielded 20 candidates, among which four compounds (Betamethasone, Lodamin, Valproxam, and Licochalcone A) reduced seizure-like activity in vivo, as assessed by behavioral assays and local field potential recordings. These effects were further evaluated in an mTOR-driven FCD model. Collectively, our findings establish a transcriptome-guided framework for linking multicellular disease signatures to candidate therapeutic strategies in refractory epilepsy.